Convenient synthesis of substituted tetrahydrofuran via Lewis base catalyzed [3 + 2] domino reactions

Abstract

A DABCO catalyzed domino reaction between 3-oxo-4-(2-oxoindolin-3-ylidene) butanoates and allenoates furnished 2,3,5-substituted tetrahydrofuran furan derivatives with oxindole moieties and two exocyclic double bonds in high yield. During this reaction, two carbon atoms and one oxygen atom of 3-oxo-4-(2-oxoindolin-3-ylidene) butanoates participated. Moreover, four isomers were synthesized and two of them can be isolated in this reaction.

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The remarkable significance of substituted tetrahydrofuran derivatives in natural products has motivated chemists to develop various approaches for their construction (Fig. 1).¹ Owing to the significance of the tetrahydrofuran scaffolds, extensive efforts have been made for the efficient synthesis of these heterocycles.² Despite the presence of various methodologies, an efficient, eco-friendly, straightforward synthetic method toward tetrahydrofuran derivatives still represents a challenging task for chemists. On the other hand, over the past decade, organocatalytic domino reactions have been used for the rapid construction of numerous pharmaceuticals, natural products, and synthetically valuable building blocks.³ Such reactions have many advantages, as they are atom-economical and have reduced synthetic steps, minimized the amount of purification required and removed the need for protecting group strategies. Among the organocatalytic domino reactions, allenoates have attracted much attention due to the versatile reaction modes. After the pioneering work of Lu's [3 + 2] cycloaddition,⁴ significant advances have been made in the organocatalytic cycloaddition reactions, such as [4 + 2], [3 + 3], and [4 + 1] cycloadditions.⁵ Furthermore, very recently, many groups have developed [3 + 2] cyclizations between allenoates and methyleneoxindoles to efficiently access spirooxindoles.⁶ Therefore, we directed our efforts toward study of the reaction between easily accessible methyleneoxindoles with allenoates.

Fig. 1 Medicinally important tetrahydrofuran derivatives.

C3-substituted oxindoles demonstrate a diverse array of biological and pharmacological activities.⁷ Accordingly, much effort has been devoted in the past years in the preparation of these compounds, especially C3 spirooxindoles via organocatalytic strategies.⁸ For example, in 2010, Chen's group reported a three-component domino reaction of methyleneoxindoles with two molecules of α,β-unsaturated aldehyde catalyzed by chiral amine, to obtain a spectrum of spirooxindoles (Scheme 1, eqn (1)).⁹ Marinetti's group developed a [3 + 2] cyclization between methyleneoxindoles and allenoates catalyzed by BINOL-derived phosphine, resulting in the formation of spirocyclopentane oxindoles (Scheme 1, eqn (2)).¹⁰ Notably, for most of examples, N-protected isatins were selected as the substrates. Therefore, the development reactions of N-without protected reactions is still highly desirable for practical synthetic application. Our group has had a long-standing interest in developing new domino reactions for construction carbocycles and heterocycles due to their versatility in medicinal chemistry, in natural product synthesis, given the recent discovery of methyleneoxindoles as versatile substrate in the organocatalytic reaction, we envisioned that domino reactions between methyleneoxindoles and allenoates would yield the desired tetrahydrofuran derivatives. Herein, we wish to report a new domino reaction of 3-oxo-4-(2-oxoindolin-3-ylidene) butanoates with allenoates to form substituted tetrahydrofuran derivatives (Scheme 1, eqn (3)).

Scheme 1 Selected examples of organocatalyzed reactions of methyleneoxindoles.

We began our study with 1a and 2a as the model substrates, and the results were summarized in Table 1. When 1a (1.0 equiv.), 2a (1.2 equiv.) and 20 mol% DABCO were stirred in THF at room temperature for 16 h, three new compounds were obtained and part of 1a was recovered based on TLC analysis (Scheme 2). All of the new products were characterized by using conventional spectroscopic methods including ¹H NMR, ¹³C NMR, DEPT-135, HMQC, NOE, HRMS (ESI), and conclusive evidence for their structure and stereochemistry was derived from single crystal X-ray analysis (Fig. 2(a)).¹¹ To our surprise, a 2,3,5-trisubstituted tetrahydrofuran derivative with two exocyclic double bonds was obtained via [3 + 2] annulation reaction with four isomers. Among these four isomers, two of them can be isolated by column chromatography (3a-E,E; 3a-Z,E (double bond configuration as evidenced by NOESY, see the ESI†)), and the third isomers (3a-E,Z) mixed with trace another isomer in some cases. In view of the surprising result and the fact that tetrahydrofuran derivatives are important compounds, it was obligatory to promote us to continue to optimize the reaction conditions.

Table 1 Screening catalysts and solvents for the domino reactions^a

Entry	Catalyst	Solvent	Time (h)	Yield^b (%)	E,E : Z,E : E,Z^c
a Unless otherwise noted, all reactions are conducted with 0.1 mmol 1a, 0.12 mmol 2a, 20 mol% catalyst in 2 mL solvents.b Isolated yields.c Determined by NMR.d 3.0 equiv. 2a was used.e Reaction temperature is 0 °C.f 10 mol% DABCO is used.
1	DABCO	THF	16	40	1 : 2 : 3
2	DMAP	THF	2	50	1 : 1 : 2
3	DBU	THF	3	0	—
4	PPh3	THF	4	Complex	—
5	DABCO	CH2Cl2	2.5	90	1 : 2 : 3
6	DABCO	EtOH	2	62	1 : 1 : 3
7	DABCO	CH3CN	6	20	1 : 2 : 3
8	DABCO	Toluene	2	30	1 : 2 : 3
9	DABCO	CHCl3	2	65	1 : 2 : 2
10	DABCO	DMSO	0.5	40	1 : 1 : 3
11^d	DABCO	CH2Cl2	2.5	78	1 : 2 : 3
12^e	DABCO	CH2Cl2	10	58	1 : 1 : 2
13^f	DABCO	CH2Cl2	10	55	1 : 1 : 2
14	9-OMe-quinine	CH2Cl2	36	74	1 : 2 : 2

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Scheme 2 Preliminary results of the [3 + 2] domino reaction.

Fig. 2 Crystal structure of 3a-E,Z (a) and 3c-E,E (b).

Among the other amines were tested (Table 1), N,N-dimethyl-4-aminopyridine (DMAP) also promoted the domino reaction to give the desired product, however, at least two unknown products also obtained (entry 2). 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) exhibited no catalytic activity (entry 3). Triphenyl phosphine used as the catalyst, resulted in a complex mixture which was hard to be analyzed (entry 4). Therefore, we selected DABCO as the best catalyst to optimize the reaction conditions further. During screening solvents, to our delight, the yield can be improved to 90% using CH₂Cl₂. While, the yields of this reaction failed to improve when using toluene, CH₃CN, CHCl₃, DMSO and EtOH (entries 6–10). Furthermore, increasing the amount of 2a to 3 equivalents yield no obviously increased (entry 11). In addition, we did the reaction at 0 °C or using 10 mol% DABCO as catalyst, a prolonged reaction time was required and the Z/E selectivity of 3a did not increased (entries 12 and 13). Finally, we used 9-OMe quninine as catalyst, the Z/E selectivity still not improved obviously (entry 14). Thus, we finally established the optimal reaction conditions for this reaction: using 20 mol% of DABCO as a catalyst and CH₂Cl₂ as a solvent to perform the reaction at room temperature.

Having this optimized condition in hand, we next focused our efforts on exploring the substrate scope with respect to substitution on both methyleneoxindoles substrate (1) and allenoates (2). The results are summarized in Table 2. We first tested the substituted groups on their benzene ring of methyleneoxindoles (1), for 5, 6 or 7 substituted substrates, the corresponding 3-tetrahydrofuran indolones have been isolated in good yields (entries 1–16, except 4).¹² Concerning the electron properties of substituents of 1, electron-neutral and electron-donating substituents were compatible under the optimized reaction condition. However, when 6-methoxyl substituted 1d was surveyed, the 3-tetrahydrofuran indolone derivatives 3j was isolated in 68% yield with longer reaction time. The reason was that the 6-methoxyl group decreased the activity of the substrate 1d (entry 10). Next, we examined the effect of substituents on N atom. N-Methyl protected substrates (1) underwent this reaction in the presence of DABCO, resulting in the corresponding 3-tetrahydrofuran indolone derivatives with excellent yields (entries 12–16). Furthermore, for the N without protecting group substrates, a slightly decreased yield was obtained, with moderate stereoselectivity (entries 1–3 and 5–11). This is because some unknown side reactions occurred. Moreover, we also examined the effect of ester group of 1, the Z/E selectivity of 3 was not increased when 1j was used (entry 18). The structure of the product 3c-E,E (Fig. 2(b)) and 3m-E,E (ESI†) were confirmed by X-ray structure analysis.¹¹

Table 2 Scope of the DABCO catalyzed domino reactions^a

Entry	1	2	Time (h)	3 Yield^b (%)	E,E : Z,E : E,Z^c
a Reaction conditions: 1 (0.1 mmol), allenoates 2 (0.12 mmol), DABCO (0.02 mmol) in 2 mL CH2Cl2 at rt.b Isolated yields.c Determined by isolated yields.
1	1a	2a	2.5	90	1 : 2 : 3
2	1a	2b	2	51	1 : 1 : 1
3	1a	2c	3	62	1 : 2 : 3
4	1a	2d	6	0	—
5	1b	2a	3	62	1 : 1 : 2
6	1b	2b	3	73	1 : 2 : 3
7	1b	2c	3	79	1 : 1 : 1
8	1c	2a	2	72	1 : 3 : 4
9	1c	2c	3	70	1 : 1 : 1
10	1d	2a	3	68	1 : 1 : 2
11	1e	2a	1.5	74	1 : 2 : 3
12	1f	2a	1	90	1 : 1 : 1
13	1f	2c	5	75	1 : 1 : 2
14	1g	2b	4	51	1 : 1 : 2
15	1g	2c	5	76	1 : 1 : 1
16	1h	2a	1	89	1 : 2 : 2
17	1i	2a	1	46	1 : 3 : 5
18	1j	2a	3	66	1 : 2 : 4

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Next, we examined the scope of the reaction with various allenoates. Benzyl buta-2,3-dienoate 2a, methyl buta-2,3-dienoate 2b, and ethyl buta-2,3-dienoate 2c were accommodated in the reaction, leading to the generation of desired products in high yields (Table 2, except entry 4). However, no desired product was isolated when tert-butyl buta-2,3-dienoate 2d was used (Table 2, entry 4).

On the basis of our experimental results and some related literature,^13,14 a possible mechanism for this domino reaction is outlined in Scheme 3. The DABCO acted as a nucleophilic trigger and attacked the β carbon of allenoates to produce the allylic carbanion intermediate A, which subsequently underwent an umpolung addition to 1a to give the intermediate B. After proton transfer from enol (OH) to carbanion (3 position), the enol anion C produced, which was through oxa-Michael addition to form D, and then elimination of DABCO to furnish the desired product 3a.

Scheme 3 Possible reaction mechanism.

Conclusions

In conclusion, we have developed a convenient and efficient organocatalytic domino strategy for the synthesis of tetrahedydrofuran derivatives containing two exocyclic double bonds from readily available and simple starting materials. From the synthetic point of view, this protocol represents an extremely simple and atom-economic way to construct four 2,3,5-trisubstituted tetrahydrofuran derivatives in one pot. Further studies on the expansion of the substrate scope, asymmetric catalytic reactions and the application of this methodology to total synthesis are currently underway and will be reported in due course.

Acknowledgements

This work was supported financially by the Natural Science Foundation of China (21403154), Natural Science Foundation of Tianjin (13JCYBJC38700), Tianjin Municipal Education Commission (20120502), and Key Laboratory of Chemical Synthesis and Pollution Control of Sichuan Province CSPC2014-4-1). Xiangtai Meng is grateful for the support from 131 talents program of Tianjin. Thanks Dr Peizhong Xie for the discussion and suggestion.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, structural proofs. CCDC 1015270 (3c-E,E), 1015271 (3a-E,Z) and 1015272 (3m-E,E). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra09249j

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